The Mycobacterium tuberculosis (“M. tb”) genome is one of the largest bacterial genomes known, including more than 4 million base pairs and nearly four thousand predicted protein coding sequences. Approximately one-third of the world's population is infected with M. tb, the causative agent of the disease tuberculosis (“TB”) in humans. Infection with M. tb is commonly the result of an uninfected person inhaling M. tb bacilli that have become airborne as a result of some action of an infected person, e.g., coughing, sneezing, spitting, or talking. Clinically, infection with M. tb in humans can be divided into three stages.
In the first stage of infection, which typically lasts from three to eight weeks, M. tb bacilli are taken up by alveolar macrophages in the lungs, where they multiply. In the second stage of the infection, which typically lasts from two to five months, M. tb multiplies within inactivated macrophages until they burst, whereupon M. tb circulates via the bloodstream to all body organs including the brain, bone marrow, and other parts of the lung. In the third stage of the infection, which typically lasts from six months to two years, the host commonly develops a cell-mediated immune response to M. tb and may experience pleurisy accompanied by severe chest pain. In the fourth stage of infection, there is either resolution of the primary complex or persistence of the infection until reactivation, which may occur many years after initial exposure to M. tb. While only 5-10% of non-immunocompromised persons exposed to TB develop active TB during their lives, it is estimated that each person with active TB infects about 10-15 others annually. Ultimately, TB causes nearly two million deaths every year and is a leading killer of HIV-infected persons.
A vaccine for tuberculosis, Bacille Calmette Guérin (“BCG”), prepared with an attenuated strain of the bovine pathogen Mycobacterium bovis, is routinely used world-wide. However, the vaccine utilizes bacteria that do not normally cause disease in humans and provides little to no protection against tuberculosis in adults. Drugs are also available to treat TB, but bacterial resistance has developed against every available drug. Moreover, multi-drug resistant (“MDR”) and extensively drug-resistant (“XDR”) strains of TB pose a serious threat to human health.